CN115286577B - Preparation method of ivabradine hydrochloride and intermediate thereof - Google Patents
Preparation method of ivabradine hydrochloride and intermediate thereof Download PDFInfo
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Abstract
The invention relates to a preparation method of ivabradine hydrochloride and an intermediate thereof, which comprises the following steps: step 1: the SM-A0 is resolved by N-acetyl-L-glutamic acid to obtain SM-A1; step 2: SM-A1 reacts with ethyl chloroformate to obtain SM-A2; step 3: reducingSM-A2byredaluminumtoobtainSM-A; step 4: theSM-AandtheSM-Barebuttedtoobtainabase; step 5: forming hydrochloride by Base under the action of ethanol solution of hydrogen chloride to obtain a BA-IBD crude product; step 6: and (3) carrying out crystal transformation on the BA-IBD crude product under the action of toluene and N-methylpyrrolidone to obtain the ivabradine hydrochloride.
Description
Technical Field
The invention relates to a preparation method of ivabradine hydrochloride and an intermediate thereof.
Background
Ivabradine hydrochloride (its chemical name: 3- (3- { [ ((7S) -3, 4-dimethoxy bicyclo [ 4.2.0)]Oct-1, 3, 5-trien-7-yl) methyl]Methylamino } propyl) -1,3,4, 5-tetrahydro-7, 8-dimethoxy-2H-3-benzoazepin-2-one hydrochloride having the formula: c (C) 27 H 36 N 2 O 5 HCl, molecular weight is molecular weight: 505.1). The earliest ivabradine hydrochloride was developed by the company Shi Weiya in france (Servier). The first time in 2005 the coated tablets were marketed in the european union under the trade name "Corlentor" and in the united kingdom at the same time under the trade name "Procoralan". The product of the original research Servier company was approved for sale in China at 29 th 2015, under the trade name of Corlentor (Ivabradine), with the following indications: is suitable for patients with NYHA II-IV grade chronic heart failure with heart contraction dysfunction, which have sinus rhythm of more than or equal to 75 times/min, and can be used in combination with standard treatment including beta-receptor blocker or in contraindication or intolerance of beta-receptor blocker treatment. The specific structure is shown as the following formula:
There have been reported methods for producing ivabradine hydrochloride in the prior art, for example, patent document 1 (CN 110483312 a) discloses a method for producing high-purity ivabradine hydrochloride and an intermediate thereof, which attempts to improve the purity of the ivabradine hydrochloride intermediate represented by formula IV, and by subjecting the system after the reduction reaction to a special refining treatment, the purity of the final product ivabradine hydrochloride produced later can be remarkably improved, and the impurity compound can be controlled within a certain range. However, this method has not been studied for factors affecting the reaction yield.
Various synthetic routes for ivabradine hydrochloride have been described in prior document 2 (synthesis of ivabradine hydrochloride, an antianginal drug, mao Dongdong. University of Shenyang, university of medical science, 5 months 2009), but specific parameters of key steps have not been focused on the effects of product yield, residual solvents, etc.
Currently, the alpha crystal form is a crystal form which is generally recognized to be stable in the discovered crystal form of the ivabradine hydrochloride, and the original research Shi Weiya company can produce a pharmaceutical preparation by using the crude drug of the crystal form. However, according to the prior art, the alpha crystal form is prepared by heating and dissolving in a mixed solvent of toluene and N-methylpyrrolidone, cooling and crystallizing, and the residual solvent is not easy to remove when the product is dried due to the very high boiling point (about 203 ℃), so that the product is easy to lower in purity due to the high temperature and long-time drying required for meeting the quality requirement of solvent residue.
Further, the yield of ivabradine hydrochloride obtained by the conventional production method is generally low, the residual solvent (NMP) is not acceptable, and further research and improvement of control of especially critical processes are strongly required to provide a novel production method of ivabradine hydrochloride and an intermediate thereof, which is different from the conventional production process.
Disclosure of Invention
The application is based on the prior art, and relates to a preparation method of an ivabradine hydrochloride intermediate shown in the following chemical formula, which comprises the following steps:
(1S)-4,5-dimethoxy-1-methylaminomethyl-benzocyclobutanehydrochloride(SM-a)isreactedwith3-(3-chloropropyl)-7,8-dimethoxy-2,3,4,5-tetrahydro-1h-3-benzoazepin-2-one(SM-b)toproduceivabradinehydrochlorideintermediate(base); the reaction product was worked up as follows:
the post-treatment comprises the steps of washing the mixed solution with sodium chloride solution, standing for layering, removing the sodium chloride solution,
wherein the concentration of the sodium chloride solution is 15-27%,
the preparation method is characterized in that the concentration of the sodium chloride solution is 15-26.5%.
The preparation method is characterized in that the concentration of the sodium chloride solution is 17-24%.
The preparation method according to the above, wherein the post-treatment further comprises the following steps:
(1) Cooling the reaction system to 25-35 ℃, adding ethyl acetate, stirring, filtering, leaching a filter cake with ethyl acetate, and mixing and stirring the leaching solution and the filtrate for 1-2 hours;
(2) Washing the mixed solution with sodium chloride solution, standing for 15-25 minutes for layering, and removing the sodium chloride solution;
(3) Anhydrous sodium sulfate is added to dry the organic phase, then the organic phase is filtered, and the filtrate is concentrated under reduced pressure at 45-50 ℃.
According to the preparation method, the method further comprises the step of crystallizing the crude product of 3- (3- { [ ((7S) -3, 4-dimethoxy bicyclo [4.2.0] oct-1, 3, 5-triene-7-yl) methyl ] methylamino } propyl) -1,3,4, 5-tetrahydro-7, 8-dimethoxy-2H-3-benzoazepin-2-one hydrochloride under the action of toluene and N-methylpyrrolidone to obtain the ivabradine hydrochloride.
The preparation method according to the above, wherein the step comprises the step of adding toluene 10 times or more of the wet product and beating at 80 to 110 ℃ for 30 to 60 minutes.
The application also relates to a preparation method of the ivabradine hydrochloride, which comprises the following steps:
step 1 is (3, 4-dimethoxy bicyclo [4.2.0] oct-1, 3, 5-triene-7-yl) methylamine hydrochloride, which is resolved by N-acetyl-L-glutamic acid to obtain (S) - (3, 4-dimethoxy bicyclo [4.2.0] oct-1, 3, 5-triene-7-yl) methylamine N-acetyl-L-glutamic acid salt;
Step 2 is the reaction of the (S) - (3, 4-dimethoxy bicyclo [4.2.0] oct-1, 3, 5-trien-7-yl) methylamine N-acetyl-L-glutamate obtained in step 1 with ethyl chloroformate to obtain (S) -ethyl ((3, 4-dimethoxy bicyclo [4.2.0] oct-1, 3, 5-trien-7-yl) methyl) carbamate;
step 3 is the reduction of the (S) -ethyl ((3, 4-dimethoxy bicyclo [4.2.0] oct-1, 3, 5-trien-7-yl) methyl) carbamate obtained in step 2 by red aluminum to obtain (1S) -4, 5-dimethoxy-1-methylaminomethyl-benzocyclobutane hydrochloride;
step 4 is the reaction of (1S) -4, 5-dimethoxy-1-methylaminomethyl-benzocyclobutane hydrochloride obtained in step 3 with 3- (3-chloropropyl) -7, 8-dimethoxy-2, 3,4, 5-tetrahydro-1H-3-benzoazepin-2-one to produce ivabradine hydrochloride intermediate (Base); the reaction product was worked up as follows: the post-treatment comprises the steps of washing the mixed solution with sodium chloride solution, standing for layering, and removing the sodium chloride solution, wherein the concentration of the sodium chloride solution is 10-26.5%;
step 5 is the hydrochloride of said Base obtained in step 4 under the action of ethanol solution of hydrogen chloride, to obtain the wet product of crude 3- (3- { [ ((7S) -3, 4-dimethoxy bicyclo [4.2.0] oct-1, 3, 5-triene-7-yl) methyl ] methylamino } propyl) -1,3,4, 5-tetrahydro-7, 8-dimethoxy-2H-3-benzoazepin-2-one hydrochloride;
Step 6 is that the wet product of the crude product of 3- (3- { [ ((7S) -3, 4-dimethoxy bicyclo [4.2.0] oct-1, 3, 5-triene-7-yl) methyl ] methylamino } propyl) -1,3,4, 5-tetrahydro-7, 8-dimethoxy-2H-3-benzoazepin-2-one hydrochloride obtained in step 5 is subjected to crystallization under the action of toluene and N-methylpyrrolidone, and the step comprises the steps of adding more than 10 times of toluene into the wet product, pulping for 30-60 minutes at 80-110 ℃, stirring and crystallizing to obtain the ivabradine hydrochloride.
The preparation method according to the above, wherein the concentration of the sodium chloride solution in the step 4 is 15% -26.5%, preferably 17% -26.5%, and more preferably 17% -24%; step 6 includes adding 10-20 times the amount of toluene to the wet product, preferably 10 times the amount of toluene to the wet product.
The preparation method according to the above, wherein the step 6 comprises the step of adding more than 10 times of toluene into the wet product and pulping for 30-60 minutes at 80-110 ℃.
The application also relates to the ivabradine hydrochloride prepared by the method.
The application discovers through repeated experiments that in the preparation process of the ivabradine hydrochloride, the reaction conditions and the like of a key preparation process are controlled, so that the product yield can be improved, the solvent residue is qualified, the production period is shortened, and the energy consumption is reduced until the application is completed.
Detailed Description
The technical solutions in the embodiments of the present application will be clearly described below in conjunction with the embodiments of the present application, and it is apparent that the described embodiments are some embodiments of the present application, but not all embodiments. All other embodiments, which are obtained by a person skilled in the art based on the embodiments of the present application, fall within the scope of protection of the present application.
The preparation process of the ivabradine hydrochloride comprises the following main steps.
Step 1 is (3, 4-dimethoxy bicyclo [4.2.0] oct-1, 3, 5-trien-7-yl) methylamine hydrochloride (CAS No: 35202-55-2, hereinafter SM-A0) resolved by N-acetyl-L-glutamic acid to obtain (S) - (3, 4-dimethoxy bicyclo [4.2.0] oct-1, 3, 5-trien-7-yl) methylamine N-acetyl-L-glutamate (hereinafter SM-A1);
in particular, the method comprises the steps of,
adding SM-A0, absolute ethyl alcohol and sodium hydroxide into a reaction kettle, stirring, filtering, adding purified water and N-acetyl-L-glutamic acid into filtrate, adding seed crystals into a system, stirring for crystallization, filtering, leaching a filter cake with absolute ethyl alcohol, pumping to obtain a filter cake, adding absolute ethyl alcohol and purified water into the filter cake, stirring, heating and heating to enable the system to flow back to the system for clarification, cooling, stirring for crystallization, filtering, and leaching the filter cake with absolute ethyl alcohol. After refining, the filter cake was drained and then dried to constant weight using air blast to obtain SM-A1.
Step 2 is to react SM-A1 with ethyl chloroformate to obtain (S) -ethyl ((3, 4-dimethoxy bicyclo [4.2.0] oct-1, 3, 5-triene-7-yl) methyl) carbamate (hereinafter referred to as SM-A2);
specifically:
adding purified water, potassium carbonate, tetrahydrofuran and SM-A1 into a reaction kettle, cooling the system, then dropwise adding tetrahydrofuran solution of ethyl chloroformate into the system, maintaining the temperature for reaction, standing the system for liquid separation after the reaction is finished, and performing aftertreatment to obtain SM-A2.
The reaction temperature is preferably-10-25 ℃, more preferably 0-5 ℃, and when the temperature is reduced, for example-15-10 ℃, the reaction system becomes sticky, the molecular kinetic energy is influenced, and the reaction efficiency is low; when the temperature is higher than the above temperature, for example, 25℃to 30℃the hydrolysis rate of ethyl chloroformate becomes high, and the reaction yield decreases.
step3istoreduceSM-A2withredaluminumtoobtain(1S)-4,5-dimethoxy-1-methylaminomethyl-benzocyclobutanehydrochloride,(hereinafterreferredtoasSM-A).
Specifically:
adding an aluminum oxide solution into a reaction kettle under the protection of nitrogen, stirring, heating to 65 ℃, dropwise adding a tetrahydrofuran solution of SM-A2, completely reacting, dropwise adding a sodium hydroxide solution, standing for liquid separation to remove a water phase, concentrating an organic phase under reduced pressure, adding absolute ethyl alcohol into a concentrate, stirring, filtering, eluting a filter cake by the absolute ethyl alcohol, combining a leaching solution with a filtrate, dropwise adding an ethanol solution of 35% sodium chloride, regulating the pH value to be 3-4, stirring for crystallization for 10 hours at 0-5 ℃, and filtering to obtain the filtrate and the filter cake. addingabsoluteethylalcoholintoafiltercake,heatingandrefluxinguntilthesystemisclarified,stoppingheating,startingtocoolto0-5℃,stirringforcrystallization,filtering,anddryingthefiltercaketoconstantweightbyblowingat45-50℃toobtainSM-A.
step4isthereactionofSM-Awith3-(3-chloropropyl)-7,8-dimethoxy-2,3,4,5-tetrahydro-1H-3-benzazepin-2-one(CASNo:85175-65-1,hereinafterreferredtoasSM-B)togive3-(3-{[((7S)-3,4-dimethoxybicyclo[4.2.0]oct-1,3,5-trien-7-yl)methyl]methylamino}propyl)-1,3,4,5-tetrahydro-7,8-dimethoxy-2H-3-benzazepin-2-one(hereinafterreferredtoasBase);
undertheprotectionofnitrogen,addingN,N-dimethylformamide,potassiumcarbonate,potassiumiodide,SM-Aandheatingandstirringintoareactionkettle,thenaddingSM-Bintothesystem,andcarryingoutthefollowingpost-treatmentafterthereactioniscompletedtoobtainbase.
(1) Cooling the reaction system to 25-35 ℃, adding ethyl acetate, stirring for 1 hour, filtering, leaching a filter cake by using ethyl acetate, and combining and stirring the leaching solution and the filtrate for 1-2 hours;
(2) Washing the mixed solution with sodium chloride solution, standing for 15-25 minutes for layering, and removing the sodium chloride solution;
(3) Anhydrous sodium sulfate is added to dry the organic phase, then the organic phase is filtered, and the filtrate is concentrated under reduced pressure at 45-50 ℃.
The inventors of the present invention have further found that, in the step of preparing ivabradine hydrochloride intermediate base, when DMF (N, N-dimethylformamide) in the organic phase is removed by using a sodium chloride water washing method, the concentration of brine is controlled to a certain range, thereby reducing the loss of the product caused by the DMF entering the aqueous phase, and significantly improving the yield in this step.
Further preferred sodium chloride solutions for washing are of the concentration: 15 to 26.5%, more preferably 17 to 26.5%, still more preferably 17 to 24%. When the concentration of the sodium chloride solution exceeds 26.5%, emulsification occurs during liquid separation, so that the yield is reduced, and when the concentration of the sodium chloride solution is lower than 10%, the product enters into an aqueous phase along with DMF, so that the yield is reduced.
Although the principle is not clear, the inventors speculate that the washing with aqueous sodium chloride solution can wash the inorganic salt in the feed solution into the aqueous phase, but at the same time wash part of the product into the aqueous phase, and relatively increase the salt concentration can reduce the solubility of the organic matter in water, but excessively increase the salt concentration can also cause the opposite technical effect.
Step 5 is the formation of hydrochloride salt of Base under the action of ethanol solution of hydrogen chloride to obtain a wet product of crude 3- (3- { [ ((7S) -3, 4-dimethoxy bicyclo [4.2.0] oct-1, 3, 5-triene-7-yl) methyl ] methylamino } propyl) -1,3,4, 5-tetrahydro-7, 8-dimethoxy-2H-3-benzoazepin-2-one hydrochloride salt (hereinafter abbreviated as BA-IBD);
specifically:
adding acetone into the concentrate produced in the step 4, transferring the dissolved feed liquid into a reaction kettle, then dropwise adding a chlorohydrin solution into the reaction kettle, stirring for crystallization, then filtering, leaching a filter cake with acetone, pumping to dryness, and drying the filter cake to constant weight by blowing at 45-50 ℃ to obtain a wet product of a BA-IBD crude product.
Step 6, carrying out crystal transformation on the wet product of the BA-IBD crude product under the action of toluene and N-methylpyrrolidone to obtain the ivabradine hydrochloride.
Specifically:
adding N-methyl pyrrolidone and BA-IBD crude product into a reaction kettle, stirring, heating, stirring, adding toluene which is more than 8 times, preferably more than 10 times and more preferably 10-20 times of wet product into the system, pulping for 30-60 minutes at 80-110 ℃ and further preferably 80-100 ℃, stirring, crystallizing, filtering, vacuum drying filter cake at 65-70 ℃ for 20-24 hours, crushing, sieving, and finally continuing vacuum drying at 65-70 ℃ to constant weight to obtain BA-IBD.
The application can ensure that the solvent residue is qualified, namely the solvent residue cannot exceed 0.053 percent by controlling the dosage of toluene, the stirring crystallization temperature and the time to proper conditions, and if the solvent residue exceeds a certain condition, the solvent residue is unqualified or other impurities are generated. The solvent residue resulting from the steps described in the present application is acceptable, so that higher temperatures and longer drying times are not required, and further, the product purity is not lowered.
Example 1
Step 1
10.0kg of SM-A0, 140.0kg of absolute ethyl alcohol and 3.7kg of sodium hydroxide are added into a 500L reaction kettle, and stirring is carried out for 3 hours at 25-30 ℃ after the addition, so that the system is in a white turbidity state. After filtration, 6.3kg of purified water and 10.7kg of N-acetyl-L-glutamic acid were added, and then 1.0g of seed crystal was added to the system to precipitate a large amount of white solid, and the mixture was stirred and crystallized for 16 hours. Filtering, putting the crystals into a Buchner funnel for filtering, eluting a filter cake with 6.0kg of absolute ethyl alcohol, and pumping to obtain the filter cake.
61.75kg of absolute ethyl alcohol and 3.25kg of purified water are added into a reaction kettle, the filter cake is added, stirring, heating and heating are carried out, the system is refluxed to be in a clear state, heating is stopped, the temperature of the system is reduced to 10-15 ℃, a large amount of solids are separated out from the system, and stirring crystallization is carried out for 3 hours at 10-15 ℃. Filtering, placing the crystal into a filter tank, carrying out suction filtration, leaching a filter cake by using 6.0kg of absolute ethyl alcohol 5, and carrying out suction drying. And (3) putting the obtained filter cake into a blast drying box, setting the temperature to 48 ℃, and drying the filter cake to constant weight at 45-50 ℃. 5.85kg of white solid SM-A1 was obtained in a yield of 35.1%.
Step 2
Opening a 100L clean reaction kettle, adding 29.3kg of purified water, 6.35kg of potassium carbonate, 15.8kg of tetrahydrofuran and 5.85kg of SM-A1 prepared in the step 1, cooling the jacket of the reaction kettle to 0-5 ℃ by opening ice salt water, and maintaining the temperature at 0-5 ℃. 7.40kg of ethyl chloroformate in tetrahydrofuran was added dropwise to the system, and the reaction was carried out after the completion of the addition. After the reaction was completed, the following post-treatments were performed: heating to 25-30 ℃, stirring for 30 min, stopping stirring, standing for 15 min, separating liquid, extracting the separated water phase with 10.45kg of ethyl acetate, stirring, standing for 15 min, separating liquid, separating the water phase, stirring and washing the organic phase with 16.7kg of saturated saline, stirring, standing for 15 min, separating liquid, separating the saline, and adding 5.85kg of anhydrous sodium sulfate into the organic phase for drying. The dried organic phase was filtered with suction in a filter tank, the filter cake was rinsed with 2.90kg of ethyl acetate, the filtrate was concentrated to dryness under reduced pressure at 45-50℃to give 3.30kg of white solid SM-A2 in a yield of 81.3%.
Step 3
9.9kg of red aluminum (70% solution) is added into a 100L reaction kettle, stirring is started, nitrogen protection is started, a jacket of the reaction kettle is heated to an internal temperature of 65 ℃, 33.0kg of SM-A2 tetrahydrofuran solution is dropwise added into the system (the preparation method comprises the steps of weighing 3.3kg of SM-A2 and dissolving in 29.7kg of tetrahydrofuran solution, stirring and dissolving), the reaction is complete, and heating is stopped. 16.6kg of aqueous sodium hydroxide solution (preparation method: 1.98kg of sodium hydroxide was weighed and dissolved in 14.6kg of purified water under stirring) was started to be added dropwise, stirred for 30 minutes, then stirring was stopped, left to stand for 15 minutes, the aqueous phase was separated, and the organic phase was concentrated to dryness under reduced pressure. 11.6kg of absolute ethyl alcohol is added into the system, stirred for 30 minutes, filtered, the filter cake is leached by 3.3kg of absolute ethyl alcohol, the leaching liquor is combined with the filtrate, then 1.25kg of 35% hydrogen chloride ethanol solution (prepared by 0.4375kg of hydrogen chloride gas and 0.8125kg of ethanol) is added dropwise, the pH value of the system is kept at 3-4, the temperature is maintained at 0-5 ℃, and the system is stirred for crystallization for 10 hours. Filtering, adding 16.0kg of absolute ethyl alcohol into the filter cake, heating until the absolute ethyl alcohol flows back until the system is clear, stopping heating, cooling the system to 0-5 ℃, and stirring and crystallizing for 3 hours at 0-5 ℃; filtering, and drying the filter cake to constant weight at 45-50 ℃ by blowing. 1.8607kgofwhitesolidSM-Awasobtainedintheyield: 61.4%.
Step 4
9.3kgofN,N-dimethylformamide,3.4kgofpotassiumcarbonateand1.27kgofpotassiumiodide,1.8607kgofSM-Awereaddedtoa30Lreactionvesselundertheprotectionofnitrogen,heatedto75℃andstirred,3.41kgofSM-Bwasthenaddedtothesystem,andaftercompletionofthereaction,thefollowingpost-treatmentwascarriedout.
After the reaction, the heating is stopped, the temperature is reduced to 25-30 ℃, 9.3kg of ethyl acetate is added into the system, and the mixture is stirred for 1 hour. Filtering, leaching the filter cake by using 9.3kg of ethyl acetate, mixing the leaching solution and the filtrate, stirring for 1-2 hours, adding 36kg of 10% sodium chloride solution (the preparation method comprises the steps of weighing 3.6kg of sodium chloride, stirring and dissolving by using 32.4kg of purified water), standing for 15 minutes, separating the sodium chloride solution, adding 1.8kg of anhydrous sodium sulfate into an organic phase, stirring and drying. Filtering, filtering sodium sulfate, concentrating the filtrate under reduced pressure at 45-50 ℃ to finally obtain 2.56kg of yellow oily Base, and obtaining the yield: 71.5%.
Step 5
To a 20L rotary evaporator containing 2.2kg of the Base prepared in step 4, 11.0kg of acetone was added for dissolution, and the dissolved feed liquid was transferred to a 30L reaction vessel. Then, 0.66kg of a 25% hydrogen chloride ethanol solution (preparation: composed of 0.165kg of hydrogen chloride gas and 0.495kg of ethanol) was added dropwise thereto, and the mixture was stirred at 0 to 5℃for crystallization for 3 hours. Filtering, leaching the filter cake with 2.2kg of acetone, pumping, taking out the filter cake, and drying the filter cake to constant weight by blowing at 45-50 ℃. 1.8007kg crude BA-IBD as white solid was obtained in yield: 75.8%.
Step 6
9.2kg of N-methylpyrrolidone and 1.8kg of BA-IBD crude product (wet product) are added into a 30L reaction kettle, stirred and heated to 55-60 ℃, stirred for 30 minutes at 55-60 ℃, 11.7kg of toluene is added into the system, and then cooled, stirred and crystallized at 0-5 ℃ for 1 hour. Filtering, heating the filter cake to 80 ℃ with 18kg (10 times of crude product) of toluene, pulping for 30 minutes, cooling to room temperature, stirring for 30 minutes, filtering, vacuum drying the filter cake at 65-70 ℃ for 20-24 hours, crushing, sieving with a 40-mesh sieve, and finally vacuum drying to constant weight at 65-70 ℃ to obtain 1.5530kg of white solid BA-IBD finished product, wherein the yield is: 86.3%. Solvent residue (NMP) was acceptable.
Example 2
The concentration of the sodium chloride solution in step 4 was adjusted to 26.5%, and the other steps and conditions were the same as in example 1, to obtain a Base yield of 78.9%. The detailed steps are as follows:
step 1
10.0kg of SM-A0, 140.0kg of absolute ethyl alcohol and 3.7kg of sodium hydroxide are added into a 500L reaction kettle, and stirring is carried out for 3 hours at 25-30 ℃ after the addition, so that the system is in a white turbidity state. After filtration, 6.3kg of purified water and 10.7kg of N-acetyl-L-glutamic acid were added, and then 1.0g of seed crystal was added to the system to precipitate a large amount of white solid, and the mixture was stirred and crystallized for 16 hours. Filtering, putting the crystals into a Buchner funnel for filtering, eluting a filter cake with 6.0kg of absolute ethyl alcohol, and pumping to obtain the filter cake.
61.75kg of absolute ethyl alcohol and 3.25kg of purified water are added into a reaction kettle, the filter cake is added, stirring, heating and heating are carried out, the system is refluxed to be in a clear state, heating is stopped, the temperature of the system is reduced to 10-15 ℃, a large amount of solids are separated out from the system, and stirring crystallization is carried out for 3 hours at 10-15 ℃. Filtering, placing the crystal into a filter tank, carrying out suction filtration, leaching a filter cake by using 6.0kg of absolute ethyl alcohol 5, and carrying out suction drying. And (3) putting the obtained filter cake into a blast drying box, setting the temperature to 48 ℃, and drying the filter cake to constant weight at 45-50 ℃. 5.85kg of white solid SM-A1 was obtained in a yield of 35.1%.
Step 2
Opening a 100L clean reaction kettle, adding 29.3kg of purified water, 6.35kg of potassium carbonate, 15.8kg of tetrahydrofuran and 5.85kg of SM-A1 prepared in the step 1, cooling the jacket of the reaction kettle to 0-5 ℃ by opening ice salt water, and maintaining the temperature at 0-5 ℃. 7.40kg of ethyl chloroformate in tetrahydrofuran was added dropwise to the system, and the reaction was carried out after the completion of the addition. After the reaction was completed, the following post-treatments were performed: heating to 25-30 ℃, stirring for 30 min, stopping stirring, standing for 15 min, separating liquid, extracting the separated water phase with 10.45kg of ethyl acetate, stirring, standing for 15 min, separating liquid, separating the water phase, stirring and washing the organic phase with 16.7kg of saturated saline, stirring, standing for 15 min, separating liquid, separating the saline, and adding 5.85kg of anhydrous sodium sulfate into the organic phase for drying. The dried organic phase was filtered with suction in a filter tank, the filter cake was rinsed with 2.90kg of ethyl acetate, the filtrate was concentrated to dryness under reduced pressure at 45-50℃to give 3.30kg of white solid SM-A2 in a yield of 81.3%.
Step 3
9.9kg of red aluminum (70% solution) is added into a 100L reaction kettle, stirring is started, nitrogen protection is started, a jacket of the reaction kettle is heated to an internal temperature of 65 ℃, 33.0kg of SM-A2 tetrahydrofuran solution is dropwise added into the system (the preparation method comprises the steps of weighing 3.3kg of SM-A2 and dissolving in 29.7kg of tetrahydrofuran solution, stirring and dissolving), the reaction is complete, and heating is stopped. 16.6kg of aqueous sodium hydroxide solution (preparation method: 1.98kg of sodium hydroxide was weighed and dissolved in 14.6kg of purified water under stirring) was started to be added dropwise, stirred for 30 minutes, then stirring was stopped, left to stand for 15 minutes, the aqueous phase was separated, and the organic phase was concentrated to dryness under reduced pressure. 11.6kg of absolute ethyl alcohol is added into the system, stirred for 30 minutes, filtered, the filter cake is leached by 3.3kg of absolute ethyl alcohol, the leaching liquor is combined with the filtrate, then 1.25kg of 35% hydrogen chloride ethanol solution (prepared by 0.4375kg of hydrogen chloride gas and 0.8125kg of ethanol) is added dropwise, the pH value of the system is kept at 3-4, the temperature is maintained at 0-5 ℃, and the system is stirred for crystallization for 10 hours. Filtering, adding 16.0kg of absolute ethyl alcohol into the filter cake, heating until the absolute ethyl alcohol flows back until the system is clear, stopping heating, cooling the system to 0-5 ℃, and stirring and crystallizing for 3 hours at 0-5 ℃; filtering, and drying the filter cake to constant weight at 45-50 ℃ by blowing. 1.8607kgofwhitesolidSM-Awasobtainedintheyield: 61.4%.
Step 4
9.3kgofN,N-dimethylformamide,3.4kgofpotassiumcarbonateand1.27kgofpotassiumiodide,1.8607kgofSM-Awereaddedtoa30Lreactionvesselundertheprotectionofnitrogen,heatedto75℃andstirred,3.41kgofSM-Bwasthenaddedtothesystem,andaftercompletionofthereaction,thefollowingpost-treatmentwascarriedout.
After the reaction, the heating is stopped, the temperature is reduced to 25-30 ℃, 9.3kg of ethyl acetate is added into the system, and the mixture is stirred for 1 hour. Filtering, eluting the filter cake by using 9.3kg of ethyl acetate, mixing and stirring the leaching solution and the filtrate for 1-2 hours, adding 36kg of 26.5% sodium chloride solution, standing for 15 minutes, separating the sodium chloride solution, adding 1.8kg of anhydrous sodium sulfate into an organic phase, stirring and drying. Filtering, filtering sodium sulfate, concentrating the filtrate under reduced pressure at 45-50 ℃ to finally obtain 2.82kg of yellow oily Base, and obtaining the yield: 78.9%.
Example 3
The concentration of the sodium chloride solution in step 4 was adjusted to 17%, and the other steps and conditions were the same as in example 1, to obtain a Base yield of 79.1%. The detailed steps are as follows:
step 1
10.0kg of SM-A0, 140.0kg of absolute ethyl alcohol and 3.7kg of sodium hydroxide are added into a 500L reaction kettle, and stirring is carried out for 3 hours at 25-30 ℃ after the addition, so that the system is in a white turbidity state. After filtration, 6.3kg of purified water and 10.7kg of N-acetyl-L-glutamic acid were added, and then 1.0g of seed crystal was added to the system to precipitate a large amount of white solid, and the mixture was stirred and crystallized for 16 hours. Filtering, putting the crystals into a Buchner funnel for filtering, eluting a filter cake with 6.0kg of absolute ethyl alcohol, and pumping to obtain the filter cake.
61.75kg of absolute ethyl alcohol and 3.25kg of purified water are added into a reaction kettle, the filter cake is added, stirring, heating and heating are carried out, the system is refluxed to be in a clear state, heating is stopped, the temperature of the system is reduced to 10-15 ℃, a large amount of solids are separated out from the system, and stirring crystallization is carried out for 3 hours at 10-15 ℃. Filtering, placing the crystal into a filter tank, carrying out suction filtration, leaching a filter cake by using 6.0kg of absolute ethyl alcohol 5, and carrying out suction drying. And (3) putting the obtained filter cake into a blast drying box, setting the temperature to 48 ℃, and drying the filter cake to constant weight at 45-50 ℃. 5.85kg of white solid SM-A1 was obtained in a yield of 35.1%.
Step 2
Opening a 100L clean reaction kettle, adding 29.3kg of purified water, 6.35kg of potassium carbonate, 15.8kg of tetrahydrofuran and 5.85kg of SM-A1 prepared in the step 1, cooling the jacket of the reaction kettle to 0-5 ℃ by opening ice salt water, and maintaining the temperature at 0-5 ℃. 7.40kg of ethyl chloroformate in tetrahydrofuran was added dropwise to the system, and the reaction was carried out after the completion of the addition. After the reaction was completed, the following post-treatments were performed: heating to 25-30 ℃, stirring for 30 min, stopping stirring, standing for 15 min, separating liquid, extracting the separated water phase with 10.45kg of ethyl acetate, stirring, standing for 15 min, separating liquid, separating the water phase, stirring and washing the organic phase with 16.7kg of saturated saline, stirring, standing for 15 min, separating liquid, separating the saline, and adding 5.85kg of anhydrous sodium sulfate into the organic phase for drying. The dried organic phase was filtered with suction in a filter tank, the filter cake was rinsed with 2.90kg of ethyl acetate, the filtrate was concentrated to dryness under reduced pressure at 45-50℃to give 3.30kg of white solid SM-A2 in a yield of 81.3%.
Step 3
9.9kg of red aluminum (70% solution) is added into a 100L reaction kettle, stirring is started, nitrogen protection is started, a jacket of the reaction kettle is heated to an internal temperature of 65 ℃, 33.0kg of SM-A2 tetrahydrofuran solution is dropwise added into the system (the preparation method comprises the steps of weighing 3.3kg of SM-A2 and dissolving in 29.7kg of tetrahydrofuran solution, stirring and dissolving), the reaction is complete, and heating is stopped. 16.6kg of aqueous sodium hydroxide solution (preparation method: 1.98kg of sodium hydroxide was weighed and dissolved in 14.6kg of purified water under stirring) was started to be added dropwise, stirred for 30 minutes, then stirring was stopped, left to stand for 15 minutes, the aqueous phase was separated, and the organic phase was concentrated to dryness under reduced pressure. 11.6kg of absolute ethyl alcohol is added into the system, stirred for 30 minutes, filtered, the filter cake is leached by 3.3kg of absolute ethyl alcohol, the leaching liquor is combined with the filtrate, then 1.25kg of 35% hydrogen chloride ethanol solution (prepared by 0.4375kg of hydrogen chloride gas and 0.8125kg of ethanol) is added dropwise, the pH value of the system is kept at 3-4, the temperature is maintained at 0-5 ℃, and the system is stirred for crystallization for 10 hours. Filtering, adding 16.0kg of absolute ethyl alcohol into the filter cake, heating until the absolute ethyl alcohol flows back until the system is clear, stopping heating, cooling the system to 0-5 ℃, and stirring and crystallizing for 3 hours at 0-5 ℃; filtering, and drying the filter cake to constant weight at 45-50 ℃ by blowing. 1.8607kgofwhitesolidSM-Awasobtainedintheyield: 61.4%.
Step 4
9.3kgofN,N-dimethylformamide,3.4kgofpotassiumcarbonateand1.27kgofpotassiumiodide,1.8607kgofSM-Awereaddedtoa30Lreactionvesselundertheprotectionofnitrogen,heatedto75℃andstirred,3.41kgofSM-Bwasthenaddedtothesystem,andaftercompletionofthereaction,thefollowingpost-treatmentwascarriedout.
After the reaction, the heating is stopped, the temperature is reduced to 25-30 ℃, 9.3kg of ethyl acetate is added into the system, and the mixture is stirred for 1 hour. Filtering, eluting the filter cake by using 9.3kg of ethyl acetate, mixing and stirring the eluting solution and the filtrate for 1-2 hours, adding 36kg of 17% sodium chloride solution, standing for 15 minutes, separating the sodium chloride solution, adding 1.8kg of anhydrous sodium sulfate into the organic phase, stirring and drying. Filtering, filtering sodium sulfate, concentrating the filtrate under reduced pressure at 45-50 ℃ to finally obtain 2.83kg of yellow oily Base, and obtaining the yield: 79.1%.
Example 4
The concentration of the sodium chloride solution in step 4 was adjusted to 24%, and the other steps and conditions were the same as in example 1, to obtain a Base yield of 79.6%. The detailed steps are as follows:
step 1
10.0kg of SM-A0, 140.0kg of absolute ethyl alcohol and 3.7kg of sodium hydroxide are added into a 500L reaction kettle, and stirring is carried out for 3 hours at 25-30 ℃ after the addition, so that the system is in a white turbidity state. After filtration, 6.3kg of purified water and 10.7kg of N-acetyl-L-glutamic acid were added, and then 1.0g of seed crystal was added to the system to precipitate a large amount of white solid, and the mixture was stirred and crystallized for 16 hours. Filtering, putting the crystals into a Buchner funnel for filtering, eluting a filter cake with 6.0kg of absolute ethyl alcohol, and pumping to obtain the filter cake.
61.75kg of absolute ethyl alcohol and 3.25kg of purified water are added into a reaction kettle, the filter cake is added, stirring, heating and heating are carried out, the system is refluxed to be in a clear state, heating is stopped, the temperature of the system is reduced to 10-15 ℃, a large amount of solids are separated out from the system, and stirring crystallization is carried out for 3 hours at 10-15 ℃. Filtering, placing the crystal into a filter tank, carrying out suction filtration, leaching a filter cake by using 6.0kg of absolute ethyl alcohol 5, and carrying out suction drying. And (3) putting the obtained filter cake into a blast drying box, setting the temperature to 48 ℃, and drying the filter cake to constant weight at 45-50 ℃. 5.85kg of white solid SM-A1 was obtained in a yield of 35.1%.
Step 2
Opening a 100L clean reaction kettle, adding 29.3kg of purified water, 6.35kg of potassium carbonate, 15.8kg of tetrahydrofuran and 5.85kg of SM-A1 prepared in the step 1, cooling the jacket of the reaction kettle to 0-5 ℃ by opening ice salt water, and maintaining the temperature at 0-5 ℃. 7.40kg of ethyl chloroformate in tetrahydrofuran was added dropwise to the system, and the reaction was carried out after the completion of the addition. After the reaction was completed, the following post-treatments were performed: heating to 25-30 ℃, stirring for 30 min, stopping stirring, standing for 15 min, separating liquid, extracting the separated water phase with 10.45kg of ethyl acetate, stirring, standing for 15 min, separating liquid, separating the water phase, stirring and washing the organic phase with 16.7kg of saturated saline, stirring, standing for 15 min, separating liquid, separating the saline, and adding 5.85kg of anhydrous sodium sulfate into the organic phase for drying. The dried organic phase was filtered with suction in a filter tank, the filter cake was rinsed with 2.90kg of ethyl acetate, the filtrate was concentrated to dryness under reduced pressure at 45-50℃to give 3.30kg of white solid SM-A2 in a yield of 81.3%.
Step 3
9.9kg of red aluminum (70% solution) is added into a 100L reaction kettle, stirring is started, nitrogen protection is started, a jacket of the reaction kettle is heated to an internal temperature of 65 ℃, 33.0kg of SM-A2 tetrahydrofuran solution is dropwise added into the system (the preparation method comprises the steps of weighing 3.3kg of SM-A2 and dissolving in 29.7kg of tetrahydrofuran solution, stirring and dissolving), the reaction is complete, and heating is stopped. 16.6kg of aqueous sodium hydroxide solution (preparation method: 1.98kg of sodium hydroxide was weighed and dissolved in 14.6kg of purified water under stirring) was started to be added dropwise, stirred for 30 minutes, then stirring was stopped, left to stand for 15 minutes, the aqueous phase was separated, and the organic phase was concentrated to dryness under reduced pressure. 11.6kg of absolute ethyl alcohol is added into the system, stirred for 30 minutes, filtered, the filter cake is leached by 3.3kg of absolute ethyl alcohol, the leaching liquor is combined with the filtrate, then 1.25kg of 35% hydrogen chloride ethanol solution (prepared by 0.4375kg of hydrogen chloride gas and 0.8125kg of ethanol) is added dropwise, the pH value of the system is kept at 3-4, the temperature is maintained at 0-5 ℃, and the system is stirred for crystallization for 10 hours. Filtering, adding 16.0kg of absolute ethyl alcohol into the filter cake, heating until the absolute ethyl alcohol flows back until the system is clear, stopping heating, cooling the system to 0-5 ℃, and stirring and crystallizing for 3 hours at 0-5 ℃; filtering, and drying the filter cake to constant weight at 45-50 ℃ by blowing. 1.8607kgofwhitesolidSM-Awasobtainedintheyield: 61.4%.
Step 4
9.3kgofN,N-dimethylformamide,3.4kgofpotassiumcarbonateand1.27kgofpotassiumiodide,1.8607kgofSM-Awereaddedtoa30Lreactionvesselundertheprotectionofnitrogen,heatedto75℃andstirred,3.41kgofSM-Bwasthenaddedtothesystem,andaftercompletionofthereaction,thefollowingpost-treatmentwascarriedout.
After the reaction, the heating is stopped, the temperature is reduced to 25-30 ℃, 9.3kg of ethyl acetate is added into the system, and the mixture is stirred for 1 hour. Filtering, eluting the filter cake by using 9.3kg of ethyl acetate, mixing and stirring the eluting solution and the filtrate for 1-2 hours, adding 36kg of 24% sodium chloride solution, standing for 15 minutes, separating the sodium chloride solution, adding 1.8kg of anhydrous sodium sulfate into the organic phase, stirring and drying. Filtering, filtering sodium sulfate, concentrating the filtrate under reduced pressure at 45-50 ℃ to finally obtain 2.85kg of yellow oily Base, and obtaining the yield: 79.6%.
Example 5
The concentration of the sodium chloride solution in the step 4 is adjusted to 27%, the other steps and conditions are the same as those in the example 1, the organic phase and the water phase are seriously emulsified during liquid separation, a thicker emulsified layer is still obtained even after the solution is fully stood, and the final Base yield is 62.3%, and the following steps are shown in detail:
step 1
10.0kg of SM-A0, 140.0kg of absolute ethyl alcohol and 3.7kg of sodium hydroxide are added into a 500L reaction kettle, and stirring is carried out for 3 hours at 25-30 ℃ after the addition, so that the system is in a white turbidity state. After filtration, 6.3kg of purified water and 10.7kg of N-acetyl-L-glutamic acid were added, and then 1.0g of seed crystal was added to the system to precipitate a large amount of white solid, and the mixture was stirred and crystallized for 16 hours. Filtering, putting the crystals into a Buchner funnel for filtering, eluting a filter cake with 6.0kg of absolute ethyl alcohol, and pumping to obtain the filter cake.
61.75kg of absolute ethyl alcohol and 3.25kg of purified water are added into a reaction kettle, the filter cake is added, stirring, heating and heating are carried out, the system is refluxed to be in a clear state, heating is stopped, the temperature of the system is reduced to 10-15 ℃, a large amount of solids are separated out from the system, and stirring crystallization is carried out for 3 hours at 10-15 ℃. Filtering, placing the crystal into a filter tank, carrying out suction filtration, leaching a filter cake by using 6.0kg of absolute ethyl alcohol 5, and carrying out suction drying. And (3) putting the obtained filter cake into a blast drying box, setting the temperature to 48 ℃, and drying the filter cake to constant weight at 45-50 ℃. 5.85kg of white solid SM-A1 was obtained in a yield of 35.1%.
Step 2
Opening a 100L clean reaction kettle, adding 29.3kg of purified water, 6.35kg of potassium carbonate, 15.8kg of tetrahydrofuran and 5.85kg of SM-A1 prepared in the step 1, cooling the jacket of the reaction kettle to 0-5 ℃ by opening ice salt water, and maintaining the temperature at 0-5 ℃. 7.40kg of ethyl chloroformate in tetrahydrofuran was added dropwise to the system, and the reaction was carried out after the completion of the addition. After the reaction was completed, the following post-treatments were performed: heating to 25-30 ℃, stirring for 30 min, stopping stirring, standing for 15 min, separating liquid, extracting the separated water phase with 10.45kg of ethyl acetate, stirring, standing for 15 min, separating liquid, separating the water phase, stirring and washing the organic phase with 16.7kg of saturated saline, stirring, standing for 15 min, separating liquid, separating the saline, and adding 5.85kg of anhydrous sodium sulfate into the organic phase for drying. The dried organic phase was filtered with suction in a filter tank, the filter cake was rinsed with 2.90kg of ethyl acetate, the filtrate was concentrated to dryness under reduced pressure at 45-50℃to give 3.30kg of white solid SM-A2 in a yield of 81.3%.
Step 3
9.9kg of red aluminum (70% solution) is added into a 100L reaction kettle, stirring is started, nitrogen protection is started, a jacket of the reaction kettle is heated to an internal temperature of 65 ℃, 33.0kg of SM-A2 tetrahydrofuran solution is dropwise added into the system (the preparation method comprises the steps of weighing 3.3kg of SM-A2 and dissolving in 29.7kg of tetrahydrofuran solution, stirring and dissolving), the reaction is complete, and heating is stopped. 16.6kg of aqueous sodium hydroxide solution (preparation method: 1.98kg of sodium hydroxide was weighed and dissolved in 14.6kg of purified water under stirring) was started to be added dropwise, stirred for 30 minutes, then stirring was stopped, left to stand for 15 minutes, the aqueous phase was separated, and the organic phase was concentrated to dryness under reduced pressure. 11.6kg of absolute ethyl alcohol is added into the system, stirred for 30 minutes, filtered, the filter cake is leached by 3.3kg of absolute ethyl alcohol, the leaching liquor is combined with the filtrate, then 1.25kg of 35% hydrogen chloride ethanol solution (prepared by 0.4375kg of hydrogen chloride gas and 0.8125kg of ethanol) is added dropwise, the pH value of the system is kept at 3-4, the temperature is maintained at 0-5 ℃, and the system is stirred for crystallization for 10 hours. Filtering, adding 16.0kg of absolute ethyl alcohol into the filter cake, heating until the absolute ethyl alcohol flows back until the system is clear, stopping heating, cooling the system to 0-5 ℃, and stirring and crystallizing for 3 hours at 0-5 ℃; filtering, and drying the filter cake to constant weight at 45-50 ℃ by blowing. 1.8607kgofwhitesolidSM-Awasobtainedintheyield: 61.4%.
Step 4
9.3kgofN,N-dimethylformamide,3.4kgofpotassiumcarbonateand1.27kgofpotassiumiodide,1.8607kgofSM-Awereaddedtoa30Lreactionvesselundertheprotectionofnitrogen,heatedto75℃andstirred,3.41kgofSM-Bwasthenaddedtothesystem,andaftercompletionofthereaction,thefollowingpost-treatmentwascarriedout.
After the reaction, the heating is stopped, the temperature is reduced to 25-30 ℃, 9.3kg of ethyl acetate is added into the system, and the mixture is stirred for 1 hour. Filtering, eluting the filter cake by using 9.3kg of ethyl acetate, combining and stirring the leaching solution and the filtrate for 1-2 hours, adding 36kg of 27% sodium chloride solution, standing for 15 minutes, separating the sodium chloride solution, adding 1.8kg of anhydrous sodium sulfate into an organic phase, stirring and drying. Filtering, filtering sodium sulfate, concentrating the filtrate under reduced pressure at 45-50 ℃ to finally obtain 2.23kg of yellow oily Base, and obtaining the yield: 62.3%.
Example 6
The concentration of the sodium chloride solution in the step 4 is adjusted to be 5%, and the other steps and conditions are the same as those in the example 1, so that the Base yield is 56.4%, and the following steps are shown in detail:
step 1
10.0kg of SM-A0, 140.0kg of absolute ethyl alcohol and 3.7kg of sodium hydroxide are added into a 500L reaction kettle, and stirring is carried out for 3 hours at 25-30 ℃ after the addition, so that the system is in a white turbidity state. After filtration, 6.3kg of purified water and 10.7kg of N-acetyl-L-glutamic acid were added, and then 1.0g of seed crystal was added to the system to precipitate a large amount of white solid, and the mixture was stirred and crystallized for 16 hours. Filtering, putting the crystals into a Buchner funnel for filtering, eluting a filter cake with 6.0kg of absolute ethyl alcohol, and pumping to obtain the filter cake.
61.75kg of absolute ethyl alcohol and 3.25kg of purified water are added into a reaction kettle, the filter cake is added, stirring, heating and heating are carried out, the system is refluxed to be in a clear state, heating is stopped, the temperature of the system is reduced to 10-15 ℃, a large amount of solids are separated out from the system, and stirring crystallization is carried out for 3 hours at 10-15 ℃. Filtering, placing the crystal into a filter tank, carrying out suction filtration, leaching a filter cake by using 6.0kg of absolute ethyl alcohol 5, and carrying out suction drying. And (3) putting the obtained filter cake into a blast drying box, setting the temperature to 48 ℃, and drying the filter cake to constant weight at 45-50 ℃. 5.85kg of white solid SM-A1 was obtained in a yield of 35.1%.
Step 2
Opening a 100L clean reaction kettle, adding 29.3kg of purified water, 6.35kg of potassium carbonate, 15.8kg of tetrahydrofuran and 5.85kg of SM-A1 prepared in the step 1, cooling the jacket of the reaction kettle to 0-5 ℃ by opening ice salt water, and maintaining the temperature at 0-5 ℃. 7.40kg of ethyl chloroformate in tetrahydrofuran was added dropwise to the system, and the reaction was carried out after the completion of the addition. After the reaction was completed, the following post-treatments were performed: heating to 25-30 ℃, stirring for 30 min, stopping stirring, standing for 15 min, separating liquid, extracting the separated water phase with 10.45kg of ethyl acetate, stirring, standing for 15 min, separating liquid, separating the water phase, stirring and washing the organic phase with 16.7kg of saturated saline, stirring, standing for 15 min, separating liquid, separating the saline, and adding 5.85kg of anhydrous sodium sulfate into the organic phase for drying. The dried organic phase was filtered with suction in a filter tank, the filter cake was rinsed with 2.90kg of ethyl acetate, the filtrate was concentrated to dryness under reduced pressure at 45-50℃to give 3.30kg of white solid SM-A2 in a yield of 81.3%.
Step 3
9.9kg of red aluminum (70% solution) is added into a 100L reaction kettle, stirring is started, nitrogen protection is started, a jacket of the reaction kettle is heated to an internal temperature of 65 ℃, 33.0kg of SM-A2 tetrahydrofuran solution is dropwise added into the system (the preparation method comprises the steps of weighing 3.3kg of SM-A2 and dissolving in 29.7kg of tetrahydrofuran solution, stirring and dissolving), the reaction is complete, and heating is stopped. 16.6kg of aqueous sodium hydroxide solution (preparation method: 1.98kg of sodium hydroxide was weighed and dissolved in 14.6kg of purified water under stirring) was started to be added dropwise, stirred for 30 minutes, then stirring was stopped, left to stand for 15 minutes, the aqueous phase was separated, and the organic phase was concentrated to dryness under reduced pressure. 11.6kg of absolute ethyl alcohol is added into the system, stirred for 30 minutes, filtered, the filter cake is leached by 3.3kg of absolute ethyl alcohol, the leaching liquor is combined with the filtrate, then 1.25kg of 35% hydrogen chloride ethanol solution (prepared by 0.4375kg of hydrogen chloride gas and 0.8125kg of ethanol) is added dropwise, the pH value of the system is kept at 3-4, the temperature is maintained at 0-5 ℃, and the system is stirred for crystallization for 10 hours. Filtering, adding 16.0kg of absolute ethyl alcohol into the filter cake, heating until the absolute ethyl alcohol flows back until the system is clear, stopping heating, cooling the system to 0-5 ℃, and stirring and crystallizing for 3 hours at 0-5 ℃; filtering, and drying the filter cake to constant weight at 45-50 ℃ by blowing. 1.8607kgofwhitesolidSM-Awasobtainedintheyield: 61.4%.
Step 4
undertheprotectionofnitrogen,9.3kgofN,N-dimethylformamide,3.4kgofpotassiumcarbonate,1.27kgofpotassiumiodideand1.8607kgofSM-Aareaddedintoa30Lreactionkettle,heatedto75℃andstirred,3.41kgofSM-Bisaddedintothesystem,andafterthereactioniscompleted,thefollowingpost-treatmentiscarriedouttoobtainkgofyellowoilybase,andtheyieldis: 56.4%.
After the reaction, the heating is stopped, the temperature is reduced to 25-30 ℃, 9.3kg of ethyl acetate is added into the system, and the mixture is stirred for 1 hour. Filtering, eluting the filter cake by using 9.3kg of ethyl acetate, mixing and stirring the eluting solution and the filtrate for 1-2 hours, adding 36kg of 5% sodium chloride solution, standing for 15 minutes, separating the sodium chloride solution, adding 1.8kg of anhydrous sodium sulfate into the organic phase, stirring and drying. Filtering, filtering sodium sulfate, concentrating the filtrate under reduced pressure at 45-50 ℃ to finally obtain 2.02kg of yellow oily Base, and obtaining the yield: 56.4%.
As can be seen from examples 1 to 6 described above, when the sodium chloride solubility is less than 10% or even less than 10%, the sodium chloride solution concentration is too low to achieve the effect of effectively dissolving the inorganic salt impurities, but too high a concentration of the sodium chloride solution results in dissolution of the product together with the impurities, resulting in a significant reduction in yield.
Example 7
The toluene amount in step 6 was adjusted to 36kg, i.e., 20 times the amount of the crude product, and the remaining steps and conditions were the same as in example 1 to obtain a white solid BA-IBD finished product, and the solvent residue (NMP) was acceptable.
Example 8
The beating temperature in the step 6 was adjusted to 110 ℃, and the other steps and conditions were the same as in the example 1, to obtain a white solid BA-IBD finished product, and the solvent residue (NMP) was qualified.
Example 9
The beating time in step 6 was adjusted to 40 minutes, and the remaining steps and conditions were the same as in example 1 to obtain a white solid BA-IBD finished product, and the solvent residue (NMP) was acceptable.
Example 10
The toluene amount in step 6 was adjusted to 9kg, i.e., 5 times the amount of the crude product, and the remaining steps and conditions were the same as in example 1 to obtain a white solid BA-IBD finished product, and the solvent residue (NMP) was unacceptable.
Example 11
The beating temperature in step 6 was adjusted to 75℃and the remaining steps and conditions were the same as in example 1 to obtain a white solid BA-IBD finished product, which was unacceptable for solvent residue (NMP).
Example 12
The pulping temperature in the step 6 is adjusted to 120 ℃, and the other steps and conditions are the same as in the example 1, so that a white solid BA-IBD finished product is obtained, and the solvent residue (NMP) is qualified, so that other impurities are generated.
Example 13
The beating time in step 6 was adjusted to 10 minutes, and the remaining steps and conditions were the same as in example 1, to obtain a white solid BA-IBD finished product, and the solvent residue (NMP) was unacceptable.
Example 14
The beating time in step 6 was adjusted to 80 minutes, and the remaining steps and conditions were the same as in example 1 to obtain a white solid BA-IBD finished product, and the solvent residue (NMP) was acceptable, yielding other impurities.
According to the above examples 1 to 6, it is seen that the NaCl concentration in step 4 has an effect on the Base yield, and that too high NaCl concentration results in severe emulsification when the organic phase and the aqueous phase are separated, and too low NaCl concentration results in a decrease in the yield of the product as DMF enters the aqueous phase.
The following table can be obtained according to examples 7-14 for the amount of toluene used in step 6, the time and temperature of beating:
according to the table, the filter cake obtained in the step 6 is treated under specific conditions, and when toluene is controlled to be 10-20 times of the crude product amount, the beating time and the beating temperature of the toluene are controlled to be in specific ranges, so that the residue is qualified, and the impurity generation amount is extremely low. Too low an amount of toluene of example 10 of 5 times the amount of the crude product would result in unacceptable solvent residue; the beating time of example 14 was too long of 80 minutes, resulting in the generation of other impurities; the beating time of example 13 was too short to be 10 minutes, and the solvent residue was unacceptable; the beating temperature of example 12 was too high at 120 ℃, resulting in the generation of other impurities; the beating temperature of example 11 was too low at 75 deg.c, resulting in unacceptable solvent residues.
While the present application has been described with reference to the above-described embodiments, it is to be understood that the same is not limited to the above-described embodiments, but rather that the same is intended to be illustrative only, and that many modifications may be made by one of ordinary skill in the art without departing from the spirit of the application and scope of the appended claims.
Claims (10)
1. The preparation method of the ivabradine hydrochloride intermediate shown in the following chemical formula 3 comprises the following steps:
(1S) -4, 5-dimethoxy-1-methylaminomethyl-benzocyclobutane hydrochloride shown in the following chemical formula 1 reacts with 3- (3-chloropropyl) -7, 8-dimethoxy-2, 3,4, 5-tetrahydro-1H-3-benzoazepin-2-one shown in the following chemical formula 2 to generate an ivabradine hydrochloride intermediate shown in the following chemical formula 3; the reaction product was worked up as follows:
the post-treatment comprises the steps of washing the reaction product by sodium chloride solution, standing for layering, removing the sodium chloride solution,
wherein the concentration of the sodium chloride solution is 10-26.5%,
。
2. the preparation method of claim 1, wherein the concentration of the sodium chloride solution is 15% -26.5%.
3. The preparation method of claim 1, wherein the concentration of the sodium chloride solution is 17% -26.5%.
4. The preparation method of claim 1, wherein the concentration of the sodium chloride solution is 17% -24%.
5. The preparation method according to any one of claims 1 to 4, wherein the post-treatment further comprises the steps of:
(1) Cooling the reaction system to 25-35 ℃, adding ethyl acetate, stirring, filtering, leaching a filter cake with ethyl acetate, and mixing and stirring the leaching solution and the filtrate for 1-2 hours;
(2) Washing the mixed solution with the sodium chloride solution with the concentration of the sodium chloride solution according to any one of claims 1-4, standing for 15-25 minutes for layering, and removing the sodium chloride solution;
(3) And adding anhydrous sodium sulfate, drying the organic phase, filtering, and concentrating the filtrate under reduced pressure at 45-50 ℃.
6. A process for the preparation of ivabradine hydrochloride, further comprising the step of seeding 3- (3- { [ ((7S) -3, 4-dimethoxy bicyclo [4.2.0] oct-1, 3, 5-trien-7-yl) methyl ] methylamino } propyl) -1,3,4, 5-tetrahydro-7, 8-dimethoxy-2H-3-benzazepin-2-one hydrochloride intermediate under the action of toluene and N-methylpyrrolidone, wherein the intermediate is obtained by the process according to any one of claims 1 to 5.
7. The preparation method according to claim 6, wherein the step comprises a step of adding toluene 10 times or more of the wet product and beating at 80 to 110 ℃ for 30 to 60 minutes.
8. A method for preparing ivabradine hydrochloride, which comprises the following steps:
step 1 is (3, 4-dimethoxy bicyclo [4.2.0] oct-1, 3, 5-triene-7-yl) methylamine hydrochloride, which is resolved by N-acetyl-L-glutamic acid to obtain (S) - (3, 4-dimethoxy bicyclo [4.2.0] oct-1, 3, 5-triene-7-yl) methylamine N-acetyl-L-glutamic acid salt;
step 2 is the reaction of the (S) - (3, 4-dimethoxy bicyclo [4.2.0] oct-1, 3, 5-trien-7-yl) methylamine N-acetyl-L-glutamate obtained in step 1 with ethyl chloroformate to obtain (S) -ethyl ((3, 4-dimethoxy bicyclo [4.2.0] oct-1, 3, 5-trien-7-yl) methyl) carbamate;
step 3 is the reduction of the (S) -ethyl ((3, 4-dimethoxy bicyclo [4.2.0] oct-1, 3, 5-trien-7-yl) methyl) carbamate obtained in step 2 by red aluminum to obtain (1S) -4, 5-dimethoxy-1-methylaminomethyl-benzocyclobutane hydrochloride;
step 4 is the reaction of (1S) -4, 5-dimethoxy-1-methylaminomethyl-benzocyclobutane hydrochloride obtained in step 3 with 3- (3-chloropropyl) -7, 8-dimethoxy-2, 3,4, 5-tetrahydro-1H-3-benzoazepin-2-one to produce ivabradine hydrochloride intermediate; the reaction product was worked up as follows: the post-treatment comprises the steps of washing the mixed solution with a sodium chloride solution, standing for layering, and removing the sodium chloride solution, wherein the concentration of the sodium chloride solution is 10-26.5%;
Step 5 is the hydrochloride salt of the ivabradine hydrochloride intermediate obtained in step 4 under the action of ethanol solution of hydrogen chloride, thus obtaining a wet product of 3- (3- { [ ((7S) -3, 4-dimethoxy bicyclo [4.2.0] oct-1, 3, 5-triene-7-yl) methyl ] methylamino } propyl) -1,3,4, 5-tetrahydro-7, 8-dimethoxy-2H-3-benzoazepin-2-one hydrochloride crude product;
step 6 is that the wet product of the 3- (3- { [ ((7S) -3, 4-dimethoxy bicyclo [4.2.0] oct-1, 3, 5-triene-7-yl) methyl ] methylamino } propyl) -1,3,4, 5-tetrahydro-7, 8-dimethoxy-2H-3-benzoazepin-2-one hydrochloride crude product obtained in step 5 is subjected to crystallization under the action of toluene and N-methylpyrrolidone, and the step comprises the steps of adding more than 10 times of toluene into the wet product, pulping for 30-60 minutes at 80-110 ℃, stirring and crystallizing to obtain the ivabradine hydrochloride.
9. The preparation method of claim 8, wherein the concentration of the sodium chloride solution in the step 4 is 15% -26.5%; and the step 6 comprises adding 10-20 times of toluene into the wet product.
10. The preparation method according to claim 8, wherein the step 6 comprises adding toluene 10 times or more of the wet product, and pulping at 80-110 ℃ for 30-60 minutes.
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